In Vitro Metabolism and Disposition of Honokiol in Rat and Human Livers

The biotransformation of honokiol, a major constituent of the bark of Magnolia officinalis, was investigated in rat and human livers. When isolated, rat livers were perfused with 10 mu M honokiol and two metabolites, namely hydroxylated honokiol conjugated with glucuronic and sulfuric acid (M1) and honokiol monoglucuronide (M2), were quantified in bile and perfusate by high-performance liquid chromatography. The hepatic extraction ratio and clearance of honokiol was very high in rat liver (E: 0.99 +/- 0.01 and 35.8 +/- 0.04 mL/min, respectively) leading to very low bioavailability (F = 0.007 +/- 0.001). M2 formation was also highly efficient in human liver microsomes [V(max)/K(m) = 78.1 +/- 6.73 mu L/(min mg)], which appeared to be catalyzed mainly by UDP-glucuronosyltransferases 1A1, A3, 1A8, and 1A10, indicating hepatic and extrahepatic glucuronidation. Monosulfation of honokiol to the minor metabolite honokiol monosulfate [V(max)/K(m) = 27.9 +/- 4.33 mu L/(min mg)] by human liver cytosol was less pronounced and is mediated by sulfotransferases 1A1* 1, 1A1* 2, 1A2, 1A3, 1B1, and 1E1. P450-mediated oxidation of honokiol by liver microsomes, however, was below detection limit. In summary, this study established that glucuronidation and sulfation are the main metabolic pathways for honokiol in rat and human liver, suggesting their major contribution to clearance in vivo. (C) 2011 Wiley-Liss, Inc. and the American Pharmacists Association J Pharm Sci 100:3505-3516, 2011